Pharmacologically active new substituted benzamides



United States Patent US. Cl. 260-559 Int. Cl. C07c 103/22, 103/30; A61k27/00 6 Claims ABSTRACT OF THE DISCLOSURE Benzamide derivatives of theformula wherein R is alkyl of from 6 to 18 carbon atoms;

R and R stand for hydrogen, alkyl of from 1 to 6 carbon atoms, phenyl,benzyl, cyclopropyl or cyclohexyl, and R and R together with the amidenitrogen may form a heterocyclic ring, such as lIl'lOI'PhOllllO,cycloheptamethyleneimino and azetidino rings.

The novel compounds have a pronounced anticonvulsant effect.

This invention relates to novel organic compounds. More particularly, itis concerned with pharmacologically active new derivatives of thebenzamide which may be represented by the following general Formula ICH3&

wherein R stands for an al-kyl radical having from 6 to 18 carbon atoms;

R and R are selected from the group consisting of hydrogen atom, alkylradicals having from 1 to 6 carbon atoms, phenyl, benzyl, cyclopropyland cyclohexyl groups, and R and R together with the amide nitrogen mayform a heterocyclic ring, such as morpholino, cycloheptamethyleneiminoand azetidino rings.

It is known that some 3,4,5-trimethoxybenzamides have tranquillantproperties (Biochem. Pharm. 11, 639 (1962); British Patent No. 837,266),but their anticonvulsant effect is very slight. It is also known thatthe 4-(C alkoxy)-3,S-dimethoxy-benzamides, the 2-alk0xy-3,4-dimethoxy-benzarnides, and the 4-(C-alkoxy)-3,5-dihalo-benzamides have hypnotic and anticonvulsant properties.

It has now been found that if in the acid part of the3,4,5-trimethoxybenzamides the methoxy group in position 4 is replacedby an alkoxy group containing from 6 to 18 carbon atoms, then thehypnotic effect disappears while the anticonvulsant effect becomesselective and more pronounced, this selectivity being very desirablebecause in the therapy there are needed compounds yw'th anticonvulsantand antiepileptic actions and without hypnotic and st-upefying sideeffects.

It has been also found that these compounds can be readily prepared byprocesses providing high yields of 3,432,549 Patented Mar. 11, 1969 pureproducts. The following procedure can be advantageously employed:

In the 4-hydroxy-3,S-dimethoxybenzoic acid or the methyl, ethyl, propyland butyl esters of this acid, the hydroxyl group in position 4 istransformed by alkyl-ation to an R 0 group, where R has the same meaningas above, and the carboxyl group of the compound is reacted with anamine of the general formula HNR R where R and R have the same meaningsas above. Before this amidation reaction, the acid or ester can betransformed to a reactive acid derivative, such as acid halide.

The sequence of alkyl ation and amidation may be reversed. In this casethe 4-hydroxy group can be advantageously protected by acylation orarylrnethylation be fore the amidation reaction, and following theamidation, before the alkylation, the protective acyl or arylmethylgroup is removed.

The alkylation of the compound having a free hydroxyl group in position4 can be preferably carried out by reacting the compound with anal'lQyl-halide, alkyl sulfonate or sulfate, in the presence of analkaline condensing agent.

Alkali hydroxydes or alkali carbonates can be preferably used asalkaline condensinlg agents in the alk-ylating reaction.

The alkylation can be preferably carried out in the presence of asolvent or a diluent, e.g. an alcohol, such as methanol, ethanol orbutanol when using an alkali hydroxide as condensing agent, or a ketonesuch as acetone, butanone or acetophenone when using an alkali carbonateas condensing agent.

The acylation of the 4-hydroxy-3,S-dimethoxybenzoic acid can be carriedout with an acid halide or acid anhydride, preferably in the presence ofa tertiary base, such as pyridine or other acid-binding agents. Thehalide or anhydride of acetic or benzoic acids may be advantageouslyused for the acylation. The acyl group can be removed by acid oralkaline hydrolysis.

The arylmethylation of the 4-hydroxy-3,S-dimethoxybenzoic acid or itsester can be advantageously carried out with an arylmethyl halide orarylmet-hyl-dimethylphenylammonium halide, in the presence of analkaline condensing agent. The arylrnethyl group can be removed from the4-arylmethoxy-3,S-dimethoxybenzamides by the aid of hydrolysis orhydrogenolysis.

The amidation for obtaining the acid amides may be carried out by themethods generally used for preparing amides. For binding the acidpossibly formed during amidation, the excess of the organic baseemployed as reaction component, or a tertiary base, such astriethylamine or alkali hydrogen carbonate, can be used.

The amidation reaction is preferably carried out in a solvent.

The novel compounds of the invention exhibit valuable pharmacologicalactivity of anticonvulsant character. They have a low toxicity, and noor only slight hypnotic and tranquilizing effects.

'I hey effectively inhibit convulsions caused by chemoconvulsants orelectrical shock. Consequently, they have a strong antiepileptic effectwithout showing any neurodepressant character.

The invention Will be described in greater detail with the aid of thefollowing examples.

EXAMPLE 1 A mixture of 53 g. of rnethyl 4hydroxy-3,5-dirnethoxybenzoate, 280 ml. of acetophenone, 56 g. ofpotassium carbonate, and 53 ml. of l-bromohexane is stirred for 17 hoursat C. After filtering the excess of acetophenone and l-bromohexane isdistilled oif with steam and the oily residue extracted with ether. Theethereal solution is washed with dilute sodium hydroxide and the etherdistilled off. The remained crude methyl 4-n-hexyloxy-3,5-

dimethoxybenzoate is boiled with 36 ml. of 43% potassium hydroxide in360 ml. of methanol for 2 hours, the methanol evaporated under reducedpressure, the residue dissolved in 600 ml. of water, extracted withether and the aqueous solution acidified. The precipitate is extractedwith chloroform, the organic layer dried over anhydrous sodium sulfateand evaporated to give 67.85 g. of 4-r1- hexyloxy-3,S-dimethoxybenzoicacid; M. P. 111-1 14 C. after recrystallization from the mixture ofacetone and petroleum ether.

4 n hexyl'oxy 3,5 dirnethoxybenzoic acid (30 g.) is boiled with 30 ml.of thionyl chloride until gas evolution is complete, then excess ofthionyl chloride is. completely distilled off under reduced pressure.The residue is oily 4-n-hexyloxy-3,5-diinethoxybenzoyl chloride.

A mixture of 10.5 g. of 4-n-hexyloxy-3,S-dimethoxybenzoyl chloride and10 ml. of dry chloroform is dropped to 200 ml. of concentrated aqueousammonium hydroxide under cooling and stirring, and stirred for further 3hours. The precipitate is filtered and dried to give 9.75 g. of4-nhexyloxy-3,S-dimethoxybenzamide; M. P. 157- 158 C.

EXAMPLE 2 A mixture of 10.5 g. of 4-n-hexyloxy-3,S-dimethoxybenzoylchloride and 100 ml. of dry chloroform is dropped to 2.1 g. ofcyclopropylarnine, 68 ml. of 6% aqueous sodium hydrogen carbonate, and34 ml. of water, stirred for 2 hours and the two phases are separated.The organic layer is washed with dilute hydrochloric acid, then withdilute alkali, dried over potassium carbonate and the solvent isdistilled to leave, as the residue, 11.6 g. ofN-(4-n-hexyloxy-3,5-dimethoxybenzoyl)-cyclopropylamine; M. P. 103- 105C. after recrystallization from acetone-petroleum ether.

EXAMPLE 3 One proceeds as described in Example 2 but, instead ofcyclopropylamine, 2.1 g. of allylamine are used. In this way 11.5 g. ofN-(4-n hexyloxy-3,S-dimethoxybenzoyl)- allylamine are obtained; M. P.66-67 C. after recrystallization from petroleum ether.

EXAMPLE 4 One proceeds as described in Example 1 but instead ofl-bromohexane, 50 ml. 1-bromoheptane are used. In this way 68.1 g. of4-n-heptyloxy-3,S-dimethoxybenzoic acid is obtained; M. P. 82-85 C.after recrystallization :from petroleum ether.

This acid (30 g.) is treated with SOCl as in Example 1 to give 31.7 g.of oily 4-n-3,5-dimethoxybenzoyl chloride.

This acid chloride (10.5 g.) is reacted with 200 ml. of ammoniumhydroxide in the same manner as in Example 1 to give 9.25 g. of4-n-heptyloxy-3,S-dimethoxybenzamide; M. P. 138-139 C.

EXAMPLE 5 From 10.5 g. of 4-n-heptyloxy-3,S-dimethoxybenzoyl chlorideand 2.1 g. of cyclopropylamine, by the procedure described in Example 2,11.2 g. of N-(4-n-heptyloxy-3,5-' dimethoxybenzoyl)-cyclopropylamine areobtained; M. P. 101-102 C. after recrystallization fromacetone-petroleum ether.

EXAMPLE 6 From 10.5 g. of 4-n-primary-heptyloxy-3,S-dimethoxybenzoylchloride and 2.1 g. of allylamine, by the procedure described in Example2, 10.9 g. of N-(4-n-heptyloxy-3,5- dimethoxybenzoyl)-allylamine areobtained; M. P. 63-66 C. when recrystallized from petroleum ether.

EXAMPLE 7 Method A One proceeds as described in Example 1, but insteadof l-bromohexane, 65 ml. of l-broniooctane are used. In this way 85.25g. of 4-n-octyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 118-120"C. when recrystallized from a mixture of butanone and petroleum ether.

This acid (30 g. is treated with thionyl chloride as in Example 1 togive 31.3 g. ofoily 4-n-octyloxy-3,5-dimethoxybenzoyl chloride.

This acid chloride (10 g.) is reacted with 200 ml. of ammonium hydroxidein the same manner as in Example 1 to give 9.9 g. of4-n-octyloxy-3,S-dimethoxybenzamidc; M.P. 144-146 C.

Method B Benzoyl chloride (63 g.) is dropped to the mixture of 48 g. ofsodium hydroxide, 800 ml. of water and 59 g. of4-hydroxy-3,S-dimethoxybenzoic acid under stirring at 0 C. The reactionmixture is stirred for further 2 hours, acidified and filtered. Theprecipitate is extracted with 1000 ml. of hot water and the insolublepart filtered and dried to give 78 g. of4-benzoyloxy-3,S-dimethoxybenzoic acid; M.P. 212-2l5 C. afterrecrystallization from acetic acid.

4 benzoyloxy 3,5-dimethoxybenzoic acid (19 g.) is boiled for 40 minuteswith 6.5 ml. of thionyl chloride and 0.3 ml. of pyridine in 19 m1. ofbenzene and worked up as in Example 1. The residue is 19.5 g. of4-benzoyloxy- 3,5 dimethoxybenzoyl chloride; M.P. 116-118 C. afterrecrystallization from petroleum ether.

The mixture of 19.5 g. of 4-benzoyloxy-3,5-dimethoxybenzoyl chloride andml. of dry benzene is dropped to 250 ml. of concentrated ammoniumhydroxide with stirring and ice-cooling and stirred for further onehour. The precipitate is filtered and dried to give 16.1 g. of 4-benzoyloxy-3,5-dimethoxybenzamide; M.P. l78-181 C. when recrystallizedfrom acetic acid.

The mixture of 10 g. of 4-benzoyloxy-3,5-dimethoxybenzamide, 50 m1. ofmethanol and 28 ml. of 10% sodium hydroxide is boiled for 15 minutes,cooled and acidfied by hydrochloric acid. The precipitate is filteredand dried to give 5.1 g. of 4-hydroxy-3,S-dimethoxybenzamide; M.P.183-185 C.

The mixture of 7.88 g. of 4-hydroxy-3,5-dimethoxybenzamide, 30 ml. ofacetophenone, 9 g. of potassium carbonate and 11 m1. of l-bromooctane isstirred for 20 hours at -140" C., cooled, filtered, and the solutionevaporated in vacuo. Ether and petroleum ether are added to the residue,the precipitate is filtered and washed With dilute sodium hydroxide andWater, and dried to give 7.55 g. of 4-n-octyloxy-3,S-dimethoxybcnzamide;M.P. 146" C.

Method C.

The solution of 7.6 g. of potassium hydroxide in 34 ml. of methanol isadded to the mixture of 15.5 g. of 4-hydroxy-3,5-dimethoxybenzoic acid,17 ml. of methanol and 15.4 ml. of benzyl chloride, boiled for 5 hoursand evaporated in vacuo. The residue is boiled for one hour with 25 ml.of 10% sodium hydroxide in 10 ml. of water, and after adding water it isextracted with ether. The aqueous layer is acidified and the precipitatefiltered and dried to give 17.1 g. of 4-benzyloxy-3,5-dimethoxybenzoylchloride; M.P. 154-156 C. after recrystallization from aqueous ethanol.

4 benzyloxy 3,5-dimethoxybenzoic acid (25 g.) is boi-led with 8.5 ml. ofthionyl chloride and 0.5 ml. of pyridine in 25 ml. of benzene for 30minutes and worked up as in Example 1 to give 26 g. of4-benzyloxy-3,5-dimethoxybenzoyl chloride; M.P. 44-45 C. afterrecrystallization from petroleum ether.

The solution of 26 g. of 4-benzyloxy-3,S-dimethoxybenzoyl chloride and70 ml. of dry benzene is reacted with 250 ml. of concentrated ammoniumhydroxide as in Example 1 to give 24 g. of4-benzyloxy-3,5-dimethoxybenzamide; M.P. 153-155 C.

4-benzyloxy-3,5-dimethoxybenzamide 10 g.) is boiled for 20 minutes with5 ml. of concentrated hydrochloric acid in 20 ml. of acetic acid. 20 ml.of water are added, then the reaction mixture is cooled and theprecipitate is filtered and dried to give 5.1 g. of4-hydroxy-3,5-dimethoxybenzamide; M.P. 181-l83 C.

4-hydroxy-3,5-dimethoxybenzamide is transformed into4-n-octyloxy-3,S-dimethoxybenzamide in the same manner as in Method B.

EXAMPLE 8 By the procedure of Example 2, from 10.3 g. of 4-noctyloxy3,5-dimethoxybenzoyl chloride and 2.1 g. of cyclopropylamine, 11.3 g. ofN-(4-N-octyloxy-3,5-dimethoxybenzoyl) cyclopropylamine is obtained; M.P.102- 104 C. after recrystallization from a mixture of acetone andpetroleum ether.

EXAMPLE 9 By the procedure of Example 2, from 10.3 g. of4-noctyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allyl amine,10.4 g. of N-(4-n-octyloxy-3,5-dimethoxybenzoyl)- allylamine isotbained; M.P. 60-63 C. when recrystallized from petroleum ether.

EXAMPLE 10 The mixture of 7.5 g. of 4-n-octyl0xy-3,S-dimethoxybenzoylchloride, 40 ml. of benzene, 135 ml. of 6% aqueous sodium hydrogencarbonate solution, 50 g. of ice and 2.7 g. of crotylamine hydrochlorideis shaken for 3 hours and worked up according to Example 2. A 7.95 g.yield of N-(4-n-octyloxy-3,S-dimethoxybenzoyl) crotylamine is obtained;M.P. 8083 C. after recrystallization from a mixture of ethyl acetate andpetroleum ether.

EXAMPLE 11 By the procedure of Example 10, from 6 g. of4-noctyloxy-3,S-dimethoxybenzoyl chloride and 1.15 g. of propargylamine,6.5 g. of N-(4-n-octyloxy-3,S-dimethoxybenzoyl) propargylamine isobtained; M.P. 84-85 C. after recrystallization from a mixture of ethylacetate and petroleum ether.

EXAMPLE 12 By the procedure of Example 10, from 13.5 g. of 4-n-octyloxy-3,S-dimethoxybenzoyl chloride and 2.75 g. of azetidine, 12 g.of oily N-(4-n-octyloxy-3,S-dimethoxybenzoyl) azetidine is obtained.

EXAMPLE 13 One proceeds as described in Example 1 but instead ofl-bromohexane, 78 g. of l-bromononane are used. In this way 80.9 g. of4-n-nonyloxy-3,S-dimethoxybenzoic acid are obtained: M.P. 83-86" C.after recrystallization from a mixture of acetone and petroleum ether.

This acid (30 g.) is transformed to 31.1 g. of the oily4-n-nonyloxy-3,S-dimethoxybenzoyl chloride according to Example 1.

By the procedure of Example 1, from 10.2 g. of 4-n-nonyloxy-3,S-dimethoxybenzoylchloride and 200 ml. of ammoniumhydroxide 9 g. of 4-n-nonyloxy-3,fi-dimethoxybenzamide are obtained;131133 C.

EXAMPLE 14 In the way described in Example 2, from 10.2 g. of4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. cyclopropylamine,10.97 g. of N- (4-n-nonyloxy-3,5-dimethoxybenzoyl) cyclopropylamine areobtained; M.P. 99-101 C., when recrystallized from a mixture of acetoneand petroleum ether.

EXAMPLE 15 By the process described in Example 2, from 10.2 g. of4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine,11.5 g. of N- (4-n-nonyloxy-3,54limethoxybenzoyl) allylamine areobtained; M.P. 64-67 C. after recrystallization from petroleum ether.

EXAMPLE 16 By the process described in Example 10, from 11 g. of4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 3.65 g.

of crotylamine hydrochloride, 11.15 g. ofN-(4-n-nonyloxy-3,5-dimethoxybenzoyl) crotylamine are obtained;

M.P. 75-77 C. after recrystallization from a mixture of ethyl acetateand petroleum ether.

EXAMPLE 17 By the process described in Example 10, from 11 g. of4-n-nonyloxy-3,S-dimethoxybenzoyl chloride and 2 g. of azetidine, 12.5g. of oily N-(4-n-nonyloxy-3,5-dimethoxybenzoyl) azetidine are obtained.

EXAMPLE 18 One proceeds as described in Example 1, but instead ofl-bromohexane, g. of l-bromodecane are used. In this way 68.6 g. of4-n-decyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 72-74 C. afterrecrystallization from aqueous methanol.

This acid (10 g.) is transformed to 10.8 g. of the oily4-n-decyloxy-3,S-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 10.8 g. of4-n-decyloxy-3,5-dimethoxybenzoyl chloride and 200 ml. of ammoniumhydroxide, 8.2 g. of 4-n-decyloxy-3,S-dimethoxybenzamide are obtained:M.P. 121122 C. after recrystallization from methanol.

EXAMPLE 19 By the process described in Example 2, from 15 g. of4-n-decyloxy-3,S-dimethoxybenzoyl chloride and 3 g. of allylamine, 13.7g. of N-(4-n-decyloxy-3,S-dimethoxybenzoyl) allylamine are obtained;M.P. 6061 C. when recrystallized from petroleum ether.

EXAMPLE 20 One proceeds as described in Example 1, but instead ofl-bromohexane, 83 g. of l-bromoundecane are used. In this way 84.1 g. of4-n-undecyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 68-70 C.when recrystallized from aqueous methanol.

This acid 10 g.) is transformed to 10.9 g. of the oily4-n-undecyloxy-3,5-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 10.9 g. of4-n-undecyloxy-3,S-dimethoxybenzoyl chloride and 200* ml. of ammoniumhydroxide, 9.3 g. of 4-n-undecyloxy-3,5-dimethoxybenzamide are obtained;M.P. -117 C.

EXAMPLE 21 EXAMPLE 22 By the process described in Example 2, from 10.1g. of 4-n-dodecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. ofcyclopropylamine, after filtering the reaction mixture and drying theprecipitate, 9.4 g. of N-(4-n-dodecyloxy-3,5- dimethoxybenzoyl)cyclopropylamine are obtained; M.P. 102-104 C.

EXAMPLE 23 By the process described in Example 2, from 10.1 g. of4-n-dodecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine,10.1 g. of N-(4-n-dodecyloxy-3,5-dimethoxybenzoyl) allylamine areobtained; M.P. 64-65 C. after recrystallization from a mixture of ethylacetate and petroleum ether.

7 EXAMPLE 24 One proceeds as described in Example 1, but instead ofl-bromohexane, 73 g. of l-bromohexadecane are used. In this Way 69 g. of4-n-hexadecyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 82-84 C.after recrystallization from methanol.

This acid (30 g.) is transformed to 30.5 g. of the oily4-n-hexadecyloxy-3,5-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 10.1 g. of4-n-hexadecyloxy-3,5-dimethoxybenzoyl chloride and 200 ml. of ammoniumhydroxide, g. of 4-n-hexadecyloxy-3,5- dimethoxybenzamide are obtained;M.P. 1l8120 C. after recrystallization from methanol.

EXAMPLE 25 By the process described in Example 24, from 10.1 g. of4-n-hexadecyl0xy-3,S-dimethoxybenzoyl chloride and 2.1 g. ofcyclopropylamine, 9.85 g. of N-(4-n-hexadecyloxy-3,5-dimethoxybenzoyl)cyclopropylamine are obtained; M.P. l08110 C. after recrystallizationfrom a mixture of ethyl acetate and petroleum ether.

EXAMPLE 26 By the process described in Example 22, from 10.1 g. of4-n-hexadecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. of allylamine,9 g. of N-(4-n-hexadecyloxy-3,5-dimethoxybenzoyl)allylamine areobtained; M.P. 79-80 C. when recrystallized from petroleum ether.

EXAMPLE 27 One proceeds as described in Example 1, but instead ofl-bromohexane, 83 ml. of l-bromooctadecane are used. In this way 79.5 g.of 4-n-octadecyloxy-3,S-dimethoxybenzoic acid are obtained; M.P. 87-89C. after recrystallization from methanol.

This acid (27 g.) is transformed to 27.3 g. of the oily4-n-octadecyloxy-3,S-dimethoxybenzoyl chloride according to Example 1.

By the process of Example 1, from 9.1 g. of 4-n-octa- 8decyloxy-3,S-dimethoxybenzoyl chloride and 200 ml. of ammoniumhydroxide, 8.8 g. of 4-n-octadecyloxy-3,5- dimethoxybenzamide areobtained; M.P. 115-117 C. when recrystallized from methanol.

EXAMPLE 28 By the process described in Example 22, from 9.1 g. of 4n-octadecyloxy-3,S-dimethoxybenzoyl chloride and 2.1 g. ofcyclopropylamine, 9.5 g. of N-(4-n-octadecyloxy- 3,5-dimethoxybenzoyl)cyclopropylamine are obtained; M.P. 109-111" C. after recrystallizationfrom a mixture of ethyl acetate and petroleum ether.

EXAMPLE 29 References Cited Vacher et al.: Med. Pharmacol. Expt., vol.12, pp. 49- (January 1965).

HENRY B. JILES, Primary Examiner.

H. I. MOATZ, Assistant Examiner.

US. Cl. X.R.

